The present invention relates to new xcex2-carboline compounds, and to pharmaceutical compositions containing them. The new compounds have a serotonergic activity on receptors of the 5-HT2 family.
Serotonin is a neurotransmitter that acts on 5-HT (5-hydroxytryptamine) receptors both centrally and peripherally. To date, fourteen sub-types of serotonin receptor have been identified and classified within seven families, 5-HT1 to 5-HT7. Of the 5-HT2 family, the sub-types 5-HT2A, 5-HT2B and 5-HT2C are known. Those sub-types play a similar role in their specificity for a large number of ligands (Trends. Pharmacol. Sci., 1995, 16, 105-110, Neuropharmacology, 1994, 33, 275-317).
Since the compounds are capable of modulating the activity of 5-HT2 receptors and especially of 5-HT2C and 5HT2B receptors they are likely to be of use in the treatment of complaints such as sleep disorders, (Psychopharmacology, 1989, 97, 436-442; Neuropharmacol., 1994, 33, 467-471), appetite disorders (Psychopharmacology, 1997, 133, 309-312), panic attacks, phobias, anxiety (Br. J. Pharmacol., 1996, 117, 427-434; Neuropharmacology, 1997, 36, 793-802), depression (Biol. Psychiatry, 1996, 39, 1000-1008; Neuroscience, 1999, 91(2), 587-597), impulsive and aggressive disorders (Pharm. Biochem. Behavior, 1991, 39, 729-736), sexual disorders (Clinical Neuropharmacology, 1997 20(3), 210-214), migraine (Progress in Drug Research, 1998, 51, 219-244, ed. Springer Verlay), schizophrenia and psychosis (Eur. J. Pharm., 1993, 245, 179-182; Biol. Psychiatry, 1998, 44, 1099-1117).
A large number of xcex2-carboline compounds have already been described in the literature. That applies more especially to Patent Application EP 0 620 223, which claims tetrahydro-pyrido-indole compounds, those compounds having a strong affinity for 5-HT2C receptors. The Patent Applications EP 0 320 079 and EP 0 300 541 claim xcex2-carboline compounds, dihydro-xcex2-carboline and tetrahydro-xcex2-carboline, which have a strong fibrinolytic activity. Finally, Patent Application WO 95/24200 describes compounds having in particular a tetrahydro-xcex2-carboline structural pattern. Those compounds are specific antagonists of 5-HT2B receptors.
In addition to the fact that the compounds of the present invention are new, they have proved to be potent selective ligands of 5-HT2 receptors and, in particular, of 5-HT2C and 5HT2B antagonists, thus rendering them potentially useful in the treatment of depression, psychosis, schizophrenia, phobia, anxiety, panic attacks, sleep disorders, appetite disorders, impulsive and aggressive disorders, sexual disorders and migraine.
The present invention relates more specifically to compounds of formula (I): 
wherein:
 represents a single or double bond capable optionally of conferring an aromatic character to the ring carrying them,
R1 represents a group selected from:
hydrogen,
linear or branched (C1-C6)alkyl,
xe2x80x94R6-aryl, xe2x80x94R6-cycloalkyl, xe2x80x94R6-heterocycle, in which groups R6 represents a linear or branched (C1-C6)alkylene group,
xe2x80x94CO2R7 wherein R7 represents a linear or branched (C1-C6)alkyl group, an aryl group, a cycloalkyl group, a heterocycle, an xe2x80x94R6-aryl group, an xe2x80x94R6-cycloalkyl group or an xe2x80x94R6-heterocycle wherein R6 is as defined hereinbefore,
xe2x80x94COR8 wherein R8 represents a hydrogen atom, a linear or branched (C1-C6)alkyl group, an aryl group, a cycloalkyl group, a heterocycle, an xe2x80x94R6-aryl group, an xe2x80x94R6-cycloalkyl group or an xe2x80x94R6-heterocycle wherein R6 is as defined hereinbefore, and
xe2x80x94CONHxe2x80x94R8 wherein R8 is as defined hereinbefore,
or R1 does not exist when the nitrogen atom carrying it is already carrying an intracyclic double bond,
R2 represents a group selected from
cyano,
xe2x80x94CO2R8 wherein R8 is as defined hereinbefore,
xe2x80x94CONHR8 wherein R8 is as defined hereinbefore,
mono(C1-C6)alkylamino(C1-C6)alkylaminocarbonyl, di(C1-C6)alkylamino-(C1-C6)-alkylaminocarbonyl, the alkyl moieties of each of which groups may be linear or branched,
xe2x80x94NR8R9 wherein R8 is as defined hereinbefore and R9 represents a group as defined for R8,
xe2x80x94NHxe2x80x94CO2R7 wherein R7 is as defined hereinbefore, and
xe2x80x94COR8 wherein R8 is as defined hereinbefore,
R3 and R4 together form a (C3-C10)cycloalkyl group,
R5 represents a hydrogen atom, a linear or branched (C1-C6)alkyl group or an aryl-(C1-C6)alkyl group in which the alkyl moiety may be linear or branched,
Ra, Rb, Rc and Rd, which may be identical or different, each represents, independently of the others, a group selected from hydrogen, halogen, linear or branched (C1-C6)alkyl, hydroxy, linear or branched (C1-C6)alkoxy, linear or branched trihalo-(C1-C6)alkyl, linear or branched trihalo-(C1-C6)alkoxy, nitro, cyano, amino, linear or branched (C1-C6)alkylamino, di(C1-C6)alkylamino in which each alkyl moiety may be linear or branched, aryl, aryl-(C1-C6)alkyl in which the alkyl moiety may be linear or branched, carboxy, linear or branched (C1-C6)alkylcarbonyloxy, linear or branched (C1-C6)acyl, aryloxy and aryl-(C1-C6)alkoxy in which the alkoxy moiety may be linear or branched,
to their isomers, and also to addition salts thereof with a pharmaceutically acceptable acid or base,
it being understood that:
xe2x80x9ccycloalkylxe2x80x9d is to be understood as a mono- or bi-cyclic group that is saturated (or optionally contains one or more unsaturations that do not confer an aromatic character to the ring system), contains from 3 to 10 carbon atoms, and is optionally substituted by one or more identical or different groups selected from halogen, hydroxy, linear or branched (C1-C6)alkyl and linear or branched (C1-C6)alkoxy,
xe2x80x9carylxe2x80x9d is to be understood as a phenyl, naphthyl, tetrahydronaphthyl, dihydronaphthyl, indenyl or indanyl group, each of those groups being optionally substituted by one or more identical or different groups selected from halogen, hydroxy, cyano, nitro, linear or branched (C1-C6)alkyl, linear or branched (C1-C6)alkoxy, amino, linear or branched (C1-C6)alkylamino, di(C1-C6)alkylamino in which each of the alkyl moieties may be linear or branched, aryloxy, aryl-(C1-C6)alkoxy which the alkoxy moiety may be linear or branched, linear or branched trihalo(C1-C6)alkyl, linear or branched (C1-C6)acyl, linear or branched (C1-C6)alkoxycarbonyl, linear or branched (C1-C6)alkylaminocarbonyl and oxo,
xe2x80x9cheterocyclexe2x80x9d is to be understood as a saturated or unsaturated, mono- or bi-cyclic group of aromatic or non-aromatic character having from 5 to 12 ring members and containing one, two or three hetero atom, identical or different, hetero atoms selected from oxygen, nitrogen and sulphur, it being understood that the heterocycle may be optionally substituted by one or more identical or different groups selected from halogen, hydroxy, linear or branched (C1-C6)alkyl, linear or branched (C1-C6)alkoxy, nitro, oxo, and amino (optionally substituted by one or two linear or branched (C1-C6)alkyl groups).
Among the heterocycles there may be mentioned, by way of indication and without implying any limitation, the groups pyridinyl, thienyl, furyl, imidazolyl, 4H-pyranyl-4-one, pyrazinyl, pyrimidinyl, isoxazolyl, tetrazolyl, pyrrolyl, pyrazolyl, quinolyl, isoquinolyl, quinazolinyl, pyrrolidinyl, piperidyl, piperazinyl, 1,2,3-thiadiazolyl, . . . .
Among the pharmaceutically acceptable acids there may be mentioned, without implying any limitation, hydrochloric acid, hydrobromic acid, sulphuric acid, phosphonic acid, acetic acid, trifluoroacetic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, glutaric acid, fumaric acid, tartaric acid, maleic acid, citric acid, ascorbic acid, oxalic acid, methanesulphonic acid, camphoric acid, etc.
Among the pharmaceutically acceptable bases there may be mentioned, without implying any limitation, sodium hydroxide, potassium hydroxide, triethylamine, tert-butylamine, etc.
According to an advantageous variant, preferred compounds of the invention are those wherein R3 and R4 together form a saturated monocyclic (C3-C10)cycloalkyl group optionally substituted by one or more groups as defined hereinbefore. Especially advantageously, R3 and R4 together form an unsubstituted saturated monocyclic (C4-C6)cycloalkyl group. Even more especially, R3 and R4 together form a cyclobutyl group.
The substituents R1 preferred in accordance with the invention are the hydrogen atom and the group xe2x80x94COR8 wherein R8 is as defined for formula (I). According to an advantageous variant, the preferred substituent R1 is the group xe2x80x94COR8a wherein R8a represents an aryl group or a heterocycle.
The substituent R2 preferred in accordance with the invention is the group xe2x80x94CO2R8 wherein R8 is as defined for formula (I). According to an advantageous variant, the preferred substituent R2 is the group xe2x80x94CO2R8b wherein R8b represents a linear or branched (C1-C6)alkyl group or cycloalkyl. Especially advantageously, R8b represents an ethyl or cyclopentyl group.
The substituent R5 preferred in accordance with the invention is the hydrogen atom.
According to an especially advantageous variant, preferred compounds of the invention are the 2,3,4,9-tetrahydro-1H-xcex2-carboline compounds of formula (Ixe2x80x2): 
wherein:
R1, R2, R3, R4, R5, Ra, Rb, Rc and Rd are as defined for formula (I).
Compounds preferred in accordance with the invention are:
cyclopentyl 1-(6-chloro-2,3,4,9-tetrahydro-1H-xcex2-carbolin-1-yl)cyclobutanecarboxylate,
ethyl 1-(6-bromo-2,3,4,9-tetrahydro-1H-xcex2-carbolin-1-yl)cyclobutanecarboxylate,
ethyl 1-[6-chloro-2-(1H-imidazol-5-ylcarbonyl)-2,3,4,9-tetrahydro-1H-xcex2-carbolin-1-yl]cyclobutanecarboxylate,
ethyl 1-(6-methyl-2,3,4,9-tetrahydro-1H-xcex2-carbolin-1-yl)cyclobutanecarboxylate,
ethyl 1-(5,6-dichloro-2,3,4,9-tetrahydro-1H-xcex2-carbolin-1-yl)cyclobutanecarboxylate,
ethyl 1-(6-chloro-2,3,4,9-tetrahydro-1H-xcex2-carbolin-1-yl)cyclobutanecarboxylate,
ethyl 1-(6,7-dichloro-2,3,4,9-tetrahydro-1H-xcex2-carbolin-1-yl)cyclobutanecarboxylate,
and ethyl 1-(6-methoxy-2,3,4,9-tetrahydro-1H-xcex2-carbolin-1-yl)cyclobutanecarboxylate.
The isomers, and also the addition salts with a pharmaceutically acceptable acid or base, of the preferred compounds form an integral part of the invention.
The invention extends also to a process for the preparation of the compounds of formula (I) which is characterised in that there is used as starting material a compound of formula (II): 
wherein Ra, Rb, Rc, Rd and R5 are as defined for formula (I),
which compound of formula (II) is reacted, in accordance with synthesis conditions of the type used for peptide coupling, with a compound of formula (III): 
wherein R3 and R4 are as defined for formula (I),
to yield a compound of formula (IV): 
wherein Ra, Rb, Rc, Rd, R3, R4 and R5 are as defined hereinbefore,
which compounds of formula (IV) are treated in the presence of phosphorus oxychloride in a solvent, such as toluene or benzene, to yield the compounds of formula (I/a), a particular case of the compounds of formula (I): 
wherein Ra, Rb, Rc, Rd, R3, R4 and R5 are as defined hereinbefore,
which compounds of formula (I/a) are:
either reduced according to the conditions conventional in organic synthesis to yield the compounds of formula (I/b), a particular case of the compounds of formula (I): 
wherein Ra, Rb, Rc, Rd, R3, R4 and R5 are as defined hereinbefore,
which compounds of formula (I/b) are treated under basic conditions in the presence of a compound of formula (V):
R1xe2x80x94Xxe2x80x83xe2x80x83(V)
wherein R1 is as defined for formula (I) and X represents a leaving group customarily used in organic synthesis,
to yield the compounds of formula (I/c), a particular case of the compounds of formula (I): 
or subjected to the action of oxidising agents customarily used in organic synthesis to yield the compounds of formula (I/d), a particular case of the compounds of formula (I): 
wherein Ra, Rb, Rc, Rd, R3, R4 and R5 are as defined hereinbefore,
the totality of the compounds of formula (I/a), (I/b), (I/c) and (I/d) constituting the compounds of formula (I/e), a particular case of the compounds of formula (I): 
wherein Ra, Rb, Rc, Rd, R1, R3, R4 and R5 are as defined for formula (I),
which compound of formula (I/e),
is subjected to the conditions of transesterification in the presence of a Lewis acid and of a compound of formula (VI):
R7xe2x80x94OHxe2x80x83xe2x80x83(VI)
wherein R7 is as defined for formula (I),
to yield the compounds of formula (1/f), a particular case of the compounds of formula (I): 
wherein Ra, Rb, Rc, Rd, R1, R3, R4, R5 and R7 are as defined hereinbefore,
or is hydrolysed under basic conditions to yield the compounds of formula (I/g), a particular case of the compounds of formula (I): 
wherein Ra, Rb, Rc, Rd, R1, R3, R4 and R5 are as defined hereinbefore, which compound of formula (I/g):
is treated according to conventional amidation conditions with a compound of formula (VII):
R8xe2x80x94NH2xe2x80x83xe2x80x83(VII)
wherein R8 is as defined for formula (I), to yield the compounds of formula (I/h), a particular case of the compounds of formula (I): 
wherein Ra, Rb, Rc, Rd, R1, R3, R4, R5 and R8 are as defined hereinbefore,
the primary amide function of which compounds of formula (I/h), in the particular case where R8 represents a hydrogen atom, is converted into a nitrile function according to the conditions conventional in organic synthesis to yield the compounds of formula (I/i), a particular case of the compounds of formula (I): 
wherein Ra, Rb, Rc, Rd, R1, R3, R4 and R5 are as defined hereinbefore,
or the carboxylic acid function of which compound of formula (I/g) is converted into an aldehyde, by a reaction sequence comprising reduction then oxidation according to the conditions customary in organic chemistry, to yield the compounds of formula (I/j), a particular case of the compounds of formula (I): 
wherein Ra, Rb, Rc, Rd, R1, R3, R4 and R5 are as defined hereinbefore,
which compound of formula (I/j) is placed in the presence of a compound of formula (VIII):
R7xe2x80x94Mxe2x80x94Xxe2x80x83xe2x80x83(VIII)
wherein R7 is as defined for formula (I), M represents a metal atom, such as an alkali metal atom or a magnesium atom, and X represents a leaving group, such as a halogen atom, to yield as intermediates the compounds of formula (IX): 
wherein Ra, Rb, Rc, Rd, R1, R3, R4, R5 and R7 are as defined hereinbefore,
which compounds of formula (IX) are oxidised by means of an oxidising agent commonly used in organic synthesis,
to yield the compounds of formula (I/k), a particular case of the compounds of formula (I): 
wherein Ra, Rb, Rc, Rd, R1, R3, R4, R5 and R7 are as defined hereinbefore,
or is treated with diphenylphosphoryl azide, in the presence of triethylamine and a compound of formula R7xe2x80x94OH (VI) as defined hereinbefore, to yield the compounds of formula (I/l), a particular case of the compounds of formula (I): 
wherein Ra, Rb, Rc, Rd, R1, R3, R4, R5 and R7 are as defined hereinbefore,
which compounds of formula (I/l), in the particular case where R7 represents a benzyl group, are subjected to hydrogenolysis conditions in the presence of palladium-on-carbon to yield the compounds of formula (I/m), a particular case of the compounds of formula (I): 
the primary amine function of which compounds of formula (I/m) is converted into a secondary or tertiary amine function, according to conventional methods, to yield the compounds of formula (I/n), a particular case of the compounds of formula (I): 
wherein Ra, Rb, Rc, Rd, R1, R3, R4, R5, R8 and R9 are as defined for formula (I), it being understood that in that case R8 and R9 do not simultaneously represent a hydrogen atom, the compounds (I/a) to (I/n) constituting the totality of the compounds of the invention, which compounds are purified, if necessary, according to a conventional purification technique, may be separated, if desired, into their different isomers according to a conventional separation technique, and are optionally converted into addition salts with a pharmaceutically acceptable acid or base.
The compounds of formulae (II), (III), (V), (VI), (VII) and (VIII) are either commercially available compounds or are compounds obtained according to known methods of organic synthesis.
The present invention relates also to pharmaceutical compositions comprising as active ingredient at least one compound of formula (I), an optical isomer thereof or an addition salt thereof with a pharmaceutically acceptable acid or base, alone or in combination with one or more pharmaceutically acceptable, inert, non-toxic excipients or carriers.
Among the pharmaceutical compositions according to the invention there may be mentioned more especially those which are suitable for oral, parenteral (intravenous, intramuscular or subcutaneous), per- or trans-cutaneous, nasal, rectal, perlingual, ocular or respiratory administration, and especially tablets or dragees, sublingual tablets, sachets, gelatin capsules, lozenges, suppositories, creams, ointments, dermal gels, injectable or drinkable preparations, aerosols, eye or nose drops, etc.
The compounds of the invention have a strong serotonergic 5HT2B/5HT2C activity and particularly 5-HT2C antagonist activity (demonstrated in the binding test, where the compounds of the invention have in particular a Ki of from 10xe2x88x927 to 10xe2x88x929 nM for that receptor). The pharmaceutical compositions containing at least one compound of formula (I) are consequently useful in the treatment of depression, psychosis, schizophrenia, phobia, anxiety, panic attacks, sleep disorders, appetite disorders, impulsive and aggressive disorders, sexual disorders and migraine.
The useful dosage varies in accordance with the age and weight of the patient, the administration route, the nature and the severity of the disorder, and the administration of any other treatments, and ranges from 0.1 mg to 500 mg per day taken in one or more administrations.